Diabetes mellitus is characterized by several abnormalities of the vascular endothelium. The cellular events leading to the abnormalities of vascular endothelium in diabetes are poorly understood. It has recently been demonstrated that vascular endothelial cells interact at several levels with insulin and the insulin-like growth factors, protein hormones whose metabolism is central to the diabetic conditions. These interactions result in two major events: (1) the protein hormones modulate several specific endothelial functions and (2) the endothelial cells transport the hormones to their tissue sites of action. Studies in this proposal are designed to determine the specialized properties of endothelial cells that allow the cell to subserve these two functions. In a series of biochemical and morphological studies, it will be specifically determined (1) whether endothelial cells possess unusual receptor subtypes, (2) the specialized complexing of internalized insulin and IGFs with other proteins, (3) the presence of unusual messenger RNAs for insulin receptors, (4) the role of serum and endogenously produced IGF-binding proteins in IGF action and transport, (5) the endothelial cell transport of insulin and IGF in diabetic conditions, and (6) the endothelial transcellular transport of insulin and the IGFs at the ultrastructural level. Thus, taken together, these studies should define the mechanisms for the uptake, function, and transport of insulin and the insulin-like growth factors by vascular endothelium in normal and diabetic states.